Signaling by the lymphotoxin (LT)/LT-beta receptor (LTIbetaR) cytokine system is required for the development and organization of lymphoid tissue. More recently, LTbetaR signaling has been shown to be critical for innate immune defense to cytomegalovirus infection (CMV). CMV has evolved mechanisms to block the induction of type I interferon (IFNalphabeta), and signaling by the LTbetaR can circumvent this block. Similar to CMV, influenza and several Bunyaviruses also inhibit production of IFNalphabeta, a function performed by their respective nonstructural (NS) proteins. We will assess the contribution of the LTbetaR in regulating innate host-defenses to influenza by utilizing mouse models genetically-deficient or pharmacologically-inhibited for signaling by the LT/LTbetaR cytokine system. Analysis of an influenza mutant lacking NS1 in these models will allow us to further dissect the relationship between LTbetaR signaling, induction of IFNalphabeta and control of influenza pathogenesis. In addition, agonistic anti-LTbetaR antibody will be tested for its ability to restore or enhance antiviral immunity in vivo. Rift Valley fever virus (RVFV) and La Crosse virus (LACV) (members of the Bunyaviridae family) both encode NSs proteins that inhibit the induction of IFNalphabeta, and variants of RVFV containing deletions in NSs are severely attenuated. The ability of LTbetaR signaling to circumvent NSs antagonism of IFNalphabeta will be examined in a tissue culture model where NSs of RVFV and LACV is expressed in the absence of viral infection. Together these approaches will yield valuable information regarding the importance of the LT/LTbetaR cytokine system in regulating innate immune responses to various biodefense category A-C pathogens, and should provide clues as to whether modulation of this pathway may be therapeutically beneficial.